James S. Fraser
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View article: Autoregulation of the MET Receptor Tyrosine Kinase by its Intracellular Juxtamembrane Domain
Autoregulation of the MET Receptor Tyrosine Kinase by its Intracellular Juxtamembrane Domain Open
Receptor Tyrosine Kinases (RTKs) are single-pass transmembrane receptors whose activation is tightly regulated by intra-domain interactions within both their extracellular and intracellular regions. The intracellular juxtamembrane domain, …
View article: Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo
Discovery of AVI-6451, a Potent and Selective Inhibitor of the SARS-CoV-2 ADP-Ribosylhydrolase Mac1 with Oral Efficacy in vivo Open
The COVID-19 pandemic made plain the need for effective antivirals acting on novel antiviral targets, among which viral macrodomains have attracted considerable attention. We recently described AVI-4206 (1), a potent and selective inhibito…
View article: Macrodomain ADP-ribose binding but not ADP-ribosylhydrolase activity is critical for chikungunya virus infection of <i>Aedes</i> mosquitoes
Macrodomain ADP-ribose binding but not ADP-ribosylhydrolase activity is critical for chikungunya virus infection of <i>Aedes</i> mosquitoes Open
Viral macrodomains are promising antiviral targets that counteract host ADP-ribosylation-mediated antiviral responses in mammals. However, their role in dual-host viruses within the mosquito vector is largely unknown. Here, we investigated…
View article: Bayesian multi-state multi-condition modeling of a protein structure based on X-ray crystallography data
Bayesian multi-state multi-condition modeling of a protein structure based on X-ray crystallography data Open
An atomic structure model of a protein can be computed from a diffraction pattern of its crystal. While most crystallographic studies produce a single set of atomic coordinates, the billions of protein molecules in a crystal sample many co…
View article: Author response: The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2
Author response: The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 Open
View article: The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 Open
SARS-CoV-2 continues to pose a threat to public health. Current therapeutics remain limited to direct acting antivirals that lack distinct mechanisms of action and are already showing signs of viral resistance. The virus encodes an ADP-rib…
View article: CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2
CACHE Challenge #3: Targeting the Nsp3 Macrodomain of SARS-CoV-2 Open
The third Critical Assessment of Computational Hit-finding Experiments (CACHE) challenged computational teams to identify chemically novel ligands targeting the macrodomain 1 of SARS-CoV-2 Nsp3, a promising coronavirus drug target. Twenty-…
View article: Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release
Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release Open
The role of amino-acid residues distant from an enzyme's active site in facilitating the complete catalytic cycle-including substrate binding, chemical transformation, and product release-remains poorly understood. Here, we investigate how…
View article: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity
Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity Open
To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a c…
View article: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity
Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity Open
To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a c…
View article: Author response: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity
Author response: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity Open
View article: Author response: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Author response: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
View article: Hybrid Antibiotics Targeting the Bacterial Ribosome
Hybrid Antibiotics Targeting the Bacterial Ribosome Open
International audience
View article: Rosace-AA: Enhancing Interpretation of Deep Mutational Scanning Data with Amino Acid Substitution and Position-Specific insights
Rosace-AA: Enhancing Interpretation of Deep Mutational Scanning Data with Amino Acid Substitution and Position-Specific insights Open
Proteins are dynamic systems whose function and behavior are sensitive to environmental conditions and often involve multiple cellular roles. Deep mutational scanning experiments generate extensive datasets to capture the functional conseq…
View article: Structure-based discovery of inhibitors of Mac1 domain of nonstructural protein-3 of SARS-CoV-2 by machine learning-augmented screening of chemical space
Structure-based discovery of inhibitors of Mac1 domain of nonstructural protein-3 of SARS-CoV-2 by machine learning-augmented screening of chemical space Open
Significant efforts have been recently dedicated to the discovery of small molecule inhibitors against the Macrodomain 1 (Mac1) of nonstructural protein 3 (NSP3) as potential antivirals for SARS-CoV-2. Thus, Mac1 has also been selected as …
View article: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
Open Reading Frame 9b (Orf9b), an accessory protein of SARS-CoV and –2, is involved in innate immune suppression through its binding to the mitochondrial receptor Translocase of Outer Membrane 70 (Tom70). Previous structural studies of Orf…
View article: Bacteriophages inhibit and evade cGAS-like immune function in bacteria
Bacteriophages inhibit and evade cGAS-like immune function in bacteria Open
View article: AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid
AcrIF11 is a potent CRISPR-specific ADP-ribosyltransferase encoded by phage and plasmid Open
Phage-encoded anti-CRISPR (Acr) proteins inhibit CRISPR-Cas systems, allowing phage replication and lysogeny maintenance. Most of the Acrs characterized to date are stable stoichiometric inhibitors. While enzymatic Acrs have been character…
View article: Author response: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Author response: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
View article: Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity
Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity Open
To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a c…
View article: Author response: Expanding automated multiconformer ligand modeling to macrocycles and fragments
Author response: Expanding automated multiconformer ligand modeling to macrocycles and fragments Open
View article: Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments
Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments Open
Small molecule ligands exhibit a diverse range of conformations in solution. Upon binding to a target protein, this conformational diversity is reduced. However, ligands can retain some degree of conformational flexibility even when bound …
View article: Author response: Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments
Author response: Expanding Automated Multiconformer Ligand Modeling to Macrocycles and Fragments Open
View article: Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning
Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning Open
The macrodomain of severe acute respiratory syndrome coronavirus 2 nonstructural protein 3 is required for viral pathogenesis and is an emerging antiviral target. We previously performed an x-ray crystallography–based fragment screen and f…
View article: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
Open Reading Frame 9b (Orf9b), an accessory protein of SARS-CoV and –2, is involved in innate immune suppression through its binding to the mitochondrial receptor Translocase of Outer Membrane 70 (Tom70). Previous structural studies of Orf…
View article: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
Open Reading Frame 9b (Orf9b), an accessory protein of SARS-CoV and –2, is involved in innate immune suppression through its binding to the mitochondrial receptor Translocase of Outer Membrane 70 (Tom70). Previous structural studies of Orf…
View article: Where and how to house big data on small fragments
Where and how to house big data on small fragments Open
Fragment screening by crystallography has recently skyrocketed. Multiple synchrotrons have built specialized screening platforms, established workflows, and assembled compound libraries. Crystallographic fragment screening is now widely ac…
View article: Improving Cryo-EM Experimental Data Fit with Automated Multiconformer Modeling for Proteins and Non-proteins
Improving Cryo-EM Experimental Data Fit with Automated Multiconformer Modeling for Proteins and Non-proteins Open
Biomolecules exchange between multiple conformational states in their folded state, crucial for their function. Traditional structural biology methods, such as X-ray crystallography and cryogenic electron microscopy (cryo-EM), produce dens…
View article: Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release
Distal mutations enhance catalysis in designed enzymes by facilitating substrate binding and product release Open
The role of amino-acid residues distant from an enzyme’s active site in facilitating the complete catalytic cycle—including substrate binding, chemical transformation, and product release— remains poorly understood. Here, we investigate ho…
View article: Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response
Coupled equilibria of dimerization and lipid binding modulate SARS Cov 2 Orf9b interactions and interferon response Open
Open Reading Frame 9b (Orf9b), an accessory protein of SARS-CoV and -2, is involved in innate immune suppression through its binding to the mitochondrial receptor Translocase of Outer Membrane 70 (Tom70). Previous structural studies of Orf…